Objective: Newborns are highly susceptible to bacterial sepsis. Mannan-binding lectin (MBL), M-, L- and H-ficolin recognize microorganisms and activate the complement system via MBL-associated serine proteases (MASPs). We investigated lectin pathway cord blood concentrations in infants with neonatal sepsis. Study design: Case-control study including 47 infants with culture-proven neonatal sepsis and 94 matched controls. MBL, M-, L-, H-ficolin, MASP-2 and MASP-3 were measured in cord blood using EIA/TRIFMA. Multivariate logistic regression was performed. Results: Infants with gram-positive sepsis had significantly lower H-ficolin cord blood concentrations compared to controls (p=0.005), while infants with gram-negative sepsis had lower MBL (p=0.084). When excluding patients with postoperative sepsis, multivariate analysis confirmed that low H-ficolin < 12000ng/ml was associated with a significant risk of gram-positive sepsis (OR 3.71, 95%-CI 1.26-10.92, p=0.017). Low MBL < 300ng/ml was associated with a significant risk of gram-negative sepsis (OR 4.39, 95%-CI 1.10-17.45, p=0.036). M-ficolin cord blood concentrations correlated with absolute phagocyte count (p< 0.001), and high M-ficolin >1000ng/ml was predictive of early-onset sepsis (OR 10.92, 95%- CI 2.21-54.02, p=0.003). The concentrations of all lectin pathway proteins increased with gestational age (p< 0.01). Conclusions: This is the first study assessing the complete lectin pathway of complement activation in invasive infections. The decreased expression of lectin pathway proteins in neonates may contribute to their extraordinary vulnerability for bacterial infections. Low MBL concentrations appear to be an important susceptibility factor for gram-negative sepsis, and low H-ficolin for gram-positive sepsis. In contrast, M-ficolin reflects phagocytic activity and was elevated in early-onset sepsis.